Unraveling underlying modes of action of early-life metal mixture exposure on child growth: integrating epidemiological and experimental evidence

Emerging epidemiological data suggest that early-life exposure to metals and metal mixtures is associated with altered fetal and child growth, but underlying modes of action (MoAs) are largely unknown.

The overall purpose of this 4-year project is to delineate underlying mechanisms of metal mixture toxicity by targeted and non-targeted approaches, combining data from a Swedish birth cohort (n=600) with an established developmental toxicity model.

Metal mixtures (cadmium, lead, methylmercury, fluoride) have been measured during pregnancy, and in the children at 4 months and 4-years using well-established exposure biomarkers.

These measurements will be related to several growth/bone-related hormones and bone remodeling markers at 4-years using statistical models designed for mixtures [Weighted Quantile Sum regression (WQS) and Bayesian Kernel Machine Regression (BKMR)].

In parallel, we will study morphological, functional and molecular effects of the metal’s mixtures on zebrafish development and growth, combining a targeted (morphometrics, hormone levels) and untargeted approach (RNAseq, metabolomics).

Altogether, this will increase our understanding of MoAs for metal-induced adverse effects on child growth and critical windows of exposure, enable us to identify novel molecular markers for key events in these MoAs, and thereby strengthen causality in epidemiological data, all which can serve as tools for future health risk monitoring and preventive actions.